Neutrophil-Dependent Oxidative Stress in Ulcerative Colitis

Medical Proteomics, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Journal of Clinical Biochemistry and Nutrition (Impact Factor: 2.19). 08/2007; 41(1):18-26. DOI: 10.3164/jcbn.2007003
Source: PubMed


Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in ulcerative colitis (UC). Current advances have defined the mechanisms by which neutrophils are activated or migrate across mucosal epithelia. A better understanding of this process will likely provide new insights into novel treatment strategies for UC. Especially, activated neutrophils produce reactive oxygen and nitrogen species within intestinal mucosa, which induce oxidative stress. In clinically, we have succeeded to develop a novel granulocytes adsorptive apheresis therapy for UC. In this article, we discuss current advances to define the role of neutrophils-dependent oxidative stress in UC.

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    • "Neutrophils are short-lived innate immune cells that have an arsenal of weapons located in preformed granules at their disposal to destroy extracellular and intracellular invading pathogens. Neutrophils are also the most abundant white blood cell in blood and produce significant quantities of cytokines [58]. As an abundant effector cell, neutrophils play an important role in IBD. "
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    ABSTRACT: Abstract The innate immune system is a key factor in understanding the pathogenesis of inflammatory bowel disease (IBD) and in the hopes of improving its treatment. NOD2, a pattern recognition receptor, was one of the first major susceptibility genes identified in Crohn's disease (CD). This discovery has been followed by genome-wide association studies that have identified other genes involved in innate immune responses. Most notably, polymorphisms in the interleukin (IL)-23 receptor have also been linked to IBD - both CD and ulcerative colitis. At the core of the innate immune defects associated with IBD is a lack of generating a robust response to control invasive commensal or pathogenic bacteria. The defect sometimes lies in a failure of the epithelium to express antimicrobial peptides or in defective control of intracellular bacteria by phagocytic cells such as dendritic cells, macrophages, or neutrophils. The recent identification of innate lymphoid cells that express the IL-23 receptor and generate both proinflammatory and protective or regulatory responses to commensal or pathogenic bacteria provides another layer of complexity to the interplay of host protection and dysregulated inflammation. Although inhibition of tumor necrosis factor has been highly successful as a strategy in treating IBD, we must better understand the nuanced role of other innate cytokines before we may incorporate these in the treatment of IBD.
    Scandinavian Journal of Gastroenterology 01/2015; 50(1):24-33. DOI:10.3109/00365521.2014.966321 · 2.36 Impact Factor
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    • "Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in UC [4]. Once large numbers of neutrophils and macrophages are activated, these cells enter the injured mucosa of the colon, leading to overproduction of reactive oxygen species (ROS) such as superoxide radical (O 2 @BULLET− ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical ( • OH) [4]. ROS are highly reactive with cell membranes. "
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    ABSTRACT: The enhanced release of reactive oxygen species from activated neutrophils plays important role in the pathogenesis of inflammatory bowel disease. We previously reported that radon inhalation activates antioxidative functions in various organs of mice. In this study, we examined the protective effects of radon inhalation on dextran sulfate sodium- (DSS) induced colitis in mice which were subjected to DSS for 7 days. Mice were continuously treated with air only (sham) or radon at a concentration of 2000 Bq/m(3) from a day before DSS administration to the end of colitis induction. In the results, radon inhalation suppressed the elevation of the disease activity index score and histological damage score induced by DSS. Based on the changes in tumor necrosis factor-alpha in plasma and myeloperoxidase activity in the colon, it was shown that radon inhalation suppressed DSS-induced colonic inflammation. Moreover, radon inhalation suppressed lipid peroxidation of the colon induced by DSS. The antioxidant level (superoxide dismutase and total glutathione) in the colon after DSS administration was significantly higher in mice treated with radon than with the sham. These results suggested that radon inhalation suppressed DSS-induced colitis through the enhancement of antioxidative functions in the colon.
    Mediators of Inflammation 12/2012; 2012(2):239617. DOI:10.1155/2012/239617 · 3.24 Impact Factor
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    • "Direct measurement of ROS in tissues is difficult because of their short biological half lives [7]. However, direct quantification of ROS levels in colon biopsy specimens from UC patients using chemiluminescence assays showed that ROS levels in these samples are increased compared to those in normal mucosa and positively correlate with disease activities [8] [9] [10] [11]. There is mounting evidence, based on analysis of nitric oxide synthase activity, that there are increased levels of RNM such as NO in inflamed inflammatory bowel disease (IBD) mucosa [12] [13] [14] [15]. "
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    ABSTRACT: In ulcerative colitis (UC), the duration and severity of inflammation are responsible for the development of colorectal cancer. Reactive oxygen species (ROS), reactive nitric metabolites (RNMs) and interleukin (IL)-8, released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Nitric oxide and peroxynitrite activate epidermal growth factor receptor (EGFR), and therapeutic agents targeted towards EGFR are currently used to treat advanced colorectal cancer. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of the proheparin-binding epidermal growth factor-like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM). The cleaved HB-EGF and C-terminal fragments (intracellular CTF) regulate proliferation via EGFR activation and nuclear export of promyelocytic leukemia zinc finger, transcription repressor, respectively. Here, we focus on the mechanisms by which RNM-and IL-8-induced EGF signaling regulate cell proliferation during the development of colitis-associated cancer.
    01/2011; 457637(6). DOI:10.1155/2011/457637
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